Biphenyl sulfonamides useful as matrix metalloproteinase...

Details Biphenyl sulfonamides useful as matrix metalloproteinase... Biphenyl sulfonamides useful as matrix metalloproteinase...

2002-02-13

2004-02-03

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C546S058000, C546S058000, C514S228200

Reexamination Certificate

active

06686355

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a group of biphenyl sulfonamide compounds and derivatives which inhibit matrix metalloproteinase enzymes and thus are useful for treating diseases resulting from connective tissue breakdown, such as heart disease, multiple sclerosis, arthritis, atherosclerosis, and osteoporosis.
BACKGROUND OF THE INVENTION
Matrix metalloproteinases (sometimes referred to as MMPs) are naturally-occurring enzymes found in most mammals. Over-expression and activation of MMPs or an imbalance between MMPs and inhibitors of MMPs have been suggested as factors in the pathogenesis of diseases characterized by the breakdown of extracellular matrix or connective tissues.
Stromelysin-1 and gelatinase A are members of the matrix metalloproteinases (MMP) family. Other members include fibroblast collagenase (MMP-1), neutrophil collagenase (MMP-8), gelatinase B (92 kDa gelatinase) (MMP-9), stromelysin-2 (MMP-10), stromelysin-3 (MMP-11), matrilysin (MMP-7), collagenase 3 (MMP-13), TNF-alpha converting enzyme (TACE), and other newly discovered membrane-associated matrix metalloproteinases (Sato H., Takino T., Okada Y., Cao J., Shinagawa A., Yamamoto E., and Seiki M.,
Nature,
1994;370:61-65). These enzymes have been implicated with a number of diseases which result from breakdown of connective tissue, including such diseases as rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, multiple sclerosis, gingivitis, corneal epidermal and gastric ulceration, atherosclerosis, neointimal proliferation which leads to restenosis and ischemic heart failure, and tumor metastasis. A method for preventing and treating these and other diseases is now recognized to be by inhibiting metalloproteinase enzymes, thereby curtailing and/or eliminating the breakdown of connective tissues that results in the disease states.
The catalytic zinc in matrix metalloproteinases is typically the focal point for inhibitor design. The modification of substrates by introducing zinc chelating groups has generated potent inhibitors such as peptide hydroxamates and thiol-containing peptides. Peptide hydroxamates and the natural endogenous inhibitors of MMPs (TIMPs) have been used successfully to treat animal models of cancer and inflammation. MMP inhibitors have also been used to prevent and treat congestive heart failure and other cardiovascular diseases, U.S. Pat. No. 5,948,780.
There is a need to discover new low molecular weight compounds that are potent inhibitors of MMP enzymes without causing undesired side effects in animals. McClure recently described a series of arylsulfonyl hydroxamic acid derivatives that are said to be useful as broad spectrum MMP inhibitors (see WO 98/34918). We now have discovered a series of biphenyl sulfonamides that are especially potent MMP inhibitors with little or no toxic effects.
SUMMARY OF THE INVENTION
In a preferred embodiment, this invention provides a group of cyclic sulfonamide compounds that are inhibitors of matrix metalloproteinase enzymes, and especially MMP-2, -3, -9, -12, -13, and -14. The invention is more particularly directed to compounds defined by Formula I
Or a pharmaceutically acceptable salt thereof,
wherein:
Each R
1
and R
2
independently are hydrogen or C
1
-C
6
alkyl;
Z is (CH
2
)
n
;
each R
3
and R
4
independently are hydrogen, halo, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl; (CH
2
)
m
OH, (CH
2
)
m
OR
5
, (CH
2
)
m
cycloalkyl, (CH
2
)
m
aryl, (CH
2
)
m
substituted aryl, (CH
2
)
m
heteroaryl, (CH
2
)
m
substituted heteroaryl, (CH
2
)
m
carbocycle, (CH
2
)
m
heterocycle; (CH
2
)
m
NR
5
R
6
, (CH
2
)
m
COR
5
, (CH
2
)
m
CONR
5
R
6
, or (CH
2
)
m
CO
2
R
5
, NO
2
, phenoxy, CN, CHO;
or two R
3
groups on adjacent carbon atoms may be taken together with the carbon atoms to which they are attached to form a ring diradical selected from:
R
5
and R
6
independently are hydrogen or C
1
-C
6
alkyl, or R
5
and R
6
taken together with the nitrogen atom to which they are attached complete a 3- to 7-membered ring containing carbon atoms, the nitrogen atom, and optionally 1 heteroatom selected from O, S, and NR
1
, wherein R
1
is as defined above;
is an integer of from 0 to 3;
m is an integer of from 0 to 6;
n is 0, 1, or 2;
Y is S, SO, or SO
2
; and
X is OH or NHOH.
Preferred compounds have Formula I wherein R
4
is hydrogen or fluoro.
A preferred group of compounds have Formula II
Wherein R
1
, R
2
, R
3
, n, p, and X are as defined above.
Especially preferred compounds have Formula II wherein R
3
is halo, particularly bromo or iodo.
An especially preferred group of compounds have Formula I wherein R
3
is alkyl substituted with amino, alkylamino, or dialkylamino. Illustrative examples include aminomethyl, 2-dimethylamino-ethyl, and 3-methylamino-butyl.
Further preferred compounds are those of Formula II, wherein two R
3
groups on adjacent carbon atoms are taken together with the carbon atoms to which they are attached to form a ring diradical selected from
Further preferred compounds are those of Formulas I or II wherein X is OH.
Still further preferred compounds have Formulas I or II wherein X is NHOH.
Another embodiment of this invention is a pharmaceutical composition, comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, admixed with a pharmaceutically acceptable carrier, excipient, or diluent. Preferred compositions comprise compounds of Formula II, or a pharmaceutically acceptable salt thereof.
Another embodiment of this invention is a method for inhibiting an MMP enzyme, comprising administering to a mammal an MMP enzyme inhibiting amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another embodiment of this invention is a method for treating a disease mediated by an MMP enzyme, comprising administering to a patient suffering from such a disease an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. Preferred methods comprise administering a compound having Formula II, or a pharmaceutically acceptable salt thereof.
A preferred method of treatment according to this invention is treatment of a disease selected from: cancer, especially breast carcinoma, inflammation, heart failure, osteoarthritis, and rheumatoid arthritis.
Another embodiment of the present invention is a compound of Formula III
Or a pharmaceutically acceptable salt thereof,
wherein:
Each R
1
and R
2
independently are hydrogen or C
1
-C
6
alkyl;
Z is (CH
2
)
n
;
each R
3
and R
4
independently are hydrogen, halo, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, (CH
2
)
m
OH, (CH
2
)
m
OR
5
, (CH
2
)
m
cycloalkyl, (CH
2
)
m
aryl, (CH
2
)
m
substituted aryl, (CH
2
)
m
heteroaryl, (CH
2
)
m
substituted heteroaryl, (CH
2
)
m
carbocycle, (CH
2
)
m
heterocycle, (CH
2
)
m
NR
5
R
6
, (CH
2
)
m
COR
5
, (CH
2
)
m
CONR
5
R
6
, or (CH
2
)
m
CO
2
R
5
, NO
2
, phenoxy, CN, CHO;
or two R
3
groups on adjacent carbon atoms may be taken together with the carbon atoms to which they are attached to form a ring diradical selected from:
R
5
and R
6
independently are hydrogen or C
1
-C
6
alkyl, or taken together with the nitrogen to which they are attached complete a 3- to 7-membered ring containing carbon atoms, the nitrogen atom, and optionally 1 heteroatom selected from O, S, and NR
1
, wherein R
1
is as defined above;
p is an integer of from 0 to 3;
m is an integer of from 0 to 6;
n is 0, 1, or 2;
Y is S, SO, or SO
2
; and
X is OH or NHOH.
A preferred group of compounds have Formula IV
Or a pharmaceutically acceptable salt thereof,
wherein:
Each R
1
and R
2
independently are hydrogen or C
1
-C
6
alkyl;
each R
3
independently is hydrogen, halo, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, (CH
2
)
m
OH, (CH
2
)
m
OR
5
, (CH
2
)
m
cycloalkyl, (CH
2
)
m
aryl, (CH
2
)
m
substituted aryl, (CH
2
)
m
heteroaryl, (CH
2
)
m
substituted heteroaryl, (CH
2
)
m
carbocycle, (CH
2
)
m
heterocycle, (CH
2
)
m
NR
5
R
6
, (CH
2
)
m
COR
5
, (CH
2
)
m
CONR
5
R
6
, or (CH
2
)
m
C
2
R
5
, NO
2
, phenoxy, CN, C

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